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Title: Molecular and functional investigation of the cystic fibrosis transmembrane conductance regulator (CFTR) in rabbit heart
Author: Davies, W. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The heterogeneous distribution of ion channels in the heart is critical for the co-ordinated conductance of electrical activity in the myocardium. Disturbances in the normal patterns of ion channel expression, in response to hypertrophic stimuli, are thought to underlie the markedly increased risk of arrhythmias in hypertrophied and failing hearts. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is expressed in the heart with an epicardial (higher) to endocardial (lower) gradient and is thought to contribute to the maintenance of the normal epicardial to endocardial gradient of repolarisation in the heart during adrenergic stress. CFTR can also modulate the activity of other ion channels. However, whether CFTR functions in this way in the heart remains unclear. CFTR exhibits many interesting features at a molecular level. In native tissue and cell lines, CFTR sustains diverse transcription start site utilisation, accompanied by differential 5' UTR usage. In adult rabbit left ventricle, the predominantly expressed CFTR isoform is the exon 5 minus alliteratively spliced variant. The objective of this study was to analysis the regional distribution of CFTR alternatively spliced variants in normal and hypertrophied hearts and to investigate its developmental regulation. Our results ascertain, for the first time, the CFTR transcripts in the heart possess multiple transcription start sites and display alternative splicing of the 5' UTR as well as exon 5. Furthermore, our results indicate that the resulting patterns of gene expression are tissue-specific, developmentally regulated and influenced by pathological stimuli. Additionally, the alternatively spliced variants display different functional characteristics that may have important implications for our understanding of CFTR function in both cardiac and epithelial tissues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available